Addition of zolpidem to combination therapy with atomoxetine‐oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial

• Published in: Respirology (Carlton, Vic.) Vic.), 2021-09, Vol.26 (9), p.878-886
• Main Authors: Messineo, Ludovico, Carter, Sophie G., Taranto‐Montemurro, Luigi, Chiang, Alan, Vakulin, Andrew, Adams, Robert J., Carberry, Jayne C., Eckert, Danny J.
• Format: Article
• Language: English
• Subjects: anti‐muscarinic; Apnea; Arousal; Ato‐Oxy; Catheters; Efficiency; noradrenergic; obstructive sleep apnoea; pharmacotherapy; Placebos; Respiration; respiratory arousal threshold; Respiratory diseases; Sleep; Sleep and wakefulness; Sleep apnea; Sleep deprivation; Sleep disorders; sleep quality; Zolpidem
• ISSN: 1323-7799; 1440-1843
• DOI: 10.1111/resp.14110

Background and objective Atomoxetine combined with oxybutynin (Ato‐Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato‐Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato‐Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next‐day sleepiness and alertness (secondary outcomes). Methods Twelve participants with OSA received 10 mg zolpidem plus Ato‐Oxy (80‐5 mg, respectively) or Ato‐Oxy plus placebo prior to overnight in‐laboratory PSG according to a double‐blind, randomized, crossover design (1‐week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next‐day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. Results The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (−26.6 ± 14.5 vs. −33.8 ± 20.3 cm H2O, p = 0.004) versus Ato‐Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next‐day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. Conclusion Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake‐promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next‐day perceived sleepiness, caution is warranted given the potential impact on next‐morning objective alertness. Combined atomoxetine and oxybutynin (Ato‐Oxy) has been shown to decrease obstructive sleep apnoea severity, yet with a slight decrease of the arousal threshold. Here, we show that the addition of zolpidem counteracted the ‘wake‐promoting’ properties of Ato‐Oxy and increased sleep efficiency and the arousal threshold, but impaired next‐day driving simulator performance. See related Editorial